1. Field of the Invention
The present invention relates to a method of selectively introducing radioactive halogen atoms into organic molecules. More particularly, the present invention relates to a method of radioiodinating organic compounds of biological interest.
2. Description of the Prior Art
Radioisotopes, particularly iodine radioisotopes have been used extensively in nuclear medicine. The preferred utility of radioiodine in nuclear medicine is based on the relative accessability of a variety of useful iodine isotopes in comparison to other radiohalogen isotopes and the availability of relatively reliable techniques of incorporating radiohalogen atoms into organic compounds. For instance, recently .omega.-iodofatty acids have been synthesized and evaluated as myocardial imaging agents. These studies have shown that certain of the halogenated acids are extracted by the myocardium as efficiently as oleic acid. Moreover, the myocardial T1/2 of the .omega.-iodofatty acids tends to be longer than the T1/2 of the .omega.-iodofatty acids because of the more remote positioning of the iodide in the .omega.-derivatives.
Traditionally, the two most frequently employed isotopes found in radiopharmaceuticals are iodine-125 and technicium-99 m. Iodine-125 is by far the most useful radioisotope because of its convenient half life of 60 days. Technicium-99 m is, however, widely utilized even though it cannot radiolabel the variety of reagents which iodine-125 is capable of labeling. In recent years, with the discovery of computerized axial tomography, short-lived positron emitting nuclides such as carbon-11, bromine-75, iodine-121 and fluorine-18 have become very important. These reagents have relatively short half lives and thus are of limited utility. (For instance, brome-75 is a useful isotope but has a half life of only 98 minutes.)
Other recent reports of introducing various radionuclides into organic molecules have been reported. All of these techniques have the common feature that a radionuclide is introduced into an organic compound by an organoborane reactant. Kabalka, G. W. et al, J. Chem. Soc., Chem. Commun., 1979, 607; Kabalka, G. W., Syn. Commun., 1980, 10, 93 and Tang et al, J. Labelled Compd. Rad., 1979, XVI, 432 have demonstrated the introduction of carbon-14, carbon-13 and carbon-11 as labeled carbon monoxide or cyanide into organic molecules by reaction of the carbon monoxide or cyanide reactant with an organoborane. Organoboranes are known to react with a variety of different chemical reagents which include mineral acids such as hydrochloric acid under rather strenuous conditions of heating the organoborane at reflux in concentrated acid. Another reaction is the anti-Markovnikov addition of halogen to an olefinic bond by the reaction of the likes of bromine with an organoborane. However, this reaction proceeds rather slowly indicating difficulty in rupturing the carbon-boron bond of the organoborane reactant by Cl.sub.2, Br.sub.2 and the like.
Receptor-binding pharmaceutical compounds are of increasing interest in nuclear medical diagnoses. In this regard there has been a recent resurgence of interest in labeled estrogen derivatives because of their potential value as agents for visualization of estrogen receptor tissues. Many of the radiolabeled estrogens are prepared by using radioiodine isotopes because of their availability and proven utility. Unfortunately, many iodinated radiopharmaceuticals deiodinate rapidly in vivo. In order to counteract this problem, increased attempts have been made to develop procedures for plating iodine at less labile sites in molecules.
Traditionally, nearly all radiohalogenated materials have been made by substitution reactions, most of which are nucleophilic. However, some useful electrophilic procedures are known. For instance, Reese et al, U.S. Pat. No. 4,192,858, show the radioiodination of triiodothyronine (T.sub.3) and Thyroxine(T.sub.4) by reaction of each of these materials with Na.sup.125 I in the presence of chloramine-T. Newman, U.S. Pat. Nos. 4,195,073 and 4,223,002, shows the use of the chloramine-T reaction in radiolabeling alpha-fetoprotein with iodine-125. Still further, Sprinkle, U.S. Pat. Nos. 4,219,538, shows a process for radioiodinating human thyroid stimulating hormone with chloramine-T and sodium iodide-125. A major disadvantage of such substitution reactions is that because the reaction rates are dependent upon the concentration of reagents, the radiohalogenation reactions do not work well on small scales. Consequently, one encounters many difficulties in synthesizing desired radiohalogenated compounds such as the rate of formation, separation of radiolabeled product from the organic starting material and side reactions such as solvent attack on the organic starting material. Yields of only 2-10% are not uncommon in such conventional synthetic procedures. Still another drawback is that the availability of suitable organic starting materials for the radiolabeling reaction is often limited. In many cases the desired substitution reaction does not occur.
An extremely important consequence of the above mentioned reaction rate problem is that no-carrier-added reagents cannot be readily prepared by most radiolabeling techniques currently in use. No-carrier-added reagents are very important because the quantity of radiopharmaceutical compound can be kept below picogram levels. This minimizes body loads and aids in the differentiation of receptor-sites, and the like. In the light of the above discussed difficulties of preparing radiohalogenated compounds by standard substitution reactions, a need continues to exist for an improved technique of radiohalogenating organic compounds in high yields from reagents which are stable.